Wnt signaling plays a critical role in normal development and cancer. This competitive renewal will determine the role played by the Wnt signaling in the formation of mesenchymal-derived lineages in the lung with an emphasis on parabronchial smooth muscle cells (PSMC). During organogenesis, the peristaltic movements generated by smooth muscle cells are essential to build up the internal pressure in the developing lung, physical force required for lung growth. Our proposal focuses on survival, proliferation and differentiation of the PSMC progenitors located in the peripheral mesenchyme during lung development. In the previous funding cycle, we have shown that these cells express Fgf10 and are located in the sub-mesothelial mesenchyme. These cells progressively relocate around the bronchi and under the influence of Bone morphogenetic 4, a growth factor expressed in the epithelium at high level and partially controlled by FGF10 itself, undergo differentiation into smooth muscle cells (Mailleux et al., 2005). In addition, we have also shown that FGF9, produced initially by the mesothelium was capable of maintaining the PSMC progenitors into an undifferentiated state both in vitro (del Moral et al., 2006) and in vivo (De Langhe et al., 2006). The key mechanistic paradigm that we will test in this proposal is that (-catenin signaling in the mesenchyme requires the formation of an active (-catenin/PITX2 transcriptional complex that will regulate the expression of Pitx2, Fgfr2 and c-Myc. In turn Fgfr2 and c-Myc are instrumental to control survival, proliferation and differentiation of PSMC progenitors. Central Hypothesis: (-catenin/PITX2 signaling axis in the mesenchyme controls survival, proliferation and differentiation of parabronchial smooth muscle cell progenitors during lung development in vivo. Aim 1: To determine the role of (-catenin signaling in the formation of the PSMCs by a loss of function approach by inactivating (-catenin throughout the lung mesenchyme (using the Dermo1Cre driver line) or in PSMC progenitors (using a Fgf10rtTA driver line). The preliminary data generated for this aim allow us to propose three sub-hypotheses that will be tested. Sub-hypothesis 1: (-catenin signaling in the mesenchyme requires the formation of a privileged (-catenin/PITX transcriptional complex. Sub-hypothesis 2: (-catenin/PITX signaling controls the expression of Fgfr2. Sub-hypothesis 3: FGFR2 signaling in the mesenchyme via PITX2 controls the formation of PSMC. HEALTH RELEVANCE: During organogenesis, the peristaltic movements generated by smooth muscle cells are essential to build up the internal pressure in the developing lung, physical force required for lung growth. Our proposal focuses on the role of (-catenin signaling in survival, proliferation and differentiation of the parabronchial smooth muscle cells progenitors located in the peripheral mesenchyme during lung development. We propose that this work will be useful to better understand pathologies where mesenchymal cells in general (whether they are undifferentiated or not) are affected. For example, abnormal proliferation of the smooth muscle cells around the bronchi occurs in several human chronic diseases such as asthma, broncho-pulmonary dysplasia and lymphangioleiomyomatosis.